Developing Inhibitors of Tankyrase Protein-Protein Interactions
Proposal
Tankyrase 1 and Tankyrase 2 are distinguishable members of the rest of the enzyme family. They share high sequence homology and have overlapping functions. There substrate biding regions consists of five ankyrin repeat clusters that are (ARC 1-5) where all of them except ARC 3 can bind to target molecules. This study seeks to develop inhibitors that can bind all the functional ARC into proteins, through the discovery that low –molecular weight fragments that bind to the ARC Tankyrase. It uses fragment optimization to generate large molecules which have additional molecule specification and high affinity.
Background
The human Tankyrase proteins (TNKS and TNKS 2) which belong to the poly (ADP ribose) polymerase (PARP) family are distinguishable from the rest of the members in this enzyme family through their structural family and the presence of a vdomain and an ankyrin protein-protein interaction domain(Lehtiö et al. 2013). They are also implicated with a multitude of cellular functions such as mitotic formation, vesicle transportation that is linked to glucose metabolism, replication and Wnt/beta‐catenin signalling. It has many proteins that are implicated in the development and maintenance of cancerous diseases. For instance, the activity of the tumour suppressor and Wnt–β‐catenin signalling is controlled by Tankyrase-dependent PARylation. .Research in the pharmacological tool so far has only been restricted to the catalytic PARP domain (Pollock et al. 2019). Additionally, some of the studies have shown that veffects are critical and that dependence on the PARP domain only achieve partial modulation of these proteins. This study addresses that the scaffolding effects of TNKS can be addressed by inhibiting the binding of Tankyrase to its substrate protein though fragment optimization.
Aims
- Determine the nodes that bind validated fragment hits to Tankyrase 1 and Tankyrase 2
- Synthesize analogues of this validated fragment hits to ensure optimization of fragment binding
- Optimization of physicochemical properties of potent compounds to get cell-molecules.
References
Lehtiö, L., Chi, N., & Krauss, S. (2013). Tankyrases as drug targets. FEBS Journal, 280(15), 3576-3593. https://doi.org/10.1111/febs.12320
Pollock, K., Liu, M., Zaleska, M., Meniconi, M., Pfuhl, M., Collins, I., & Guettler, S. (2019). Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of Tankyrase. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-55240-5